Hindawi Publishing Corporation Case Reports in Genetics Volume 2016, Article ID 9790169, 6 pages http://dx.doi.org/10.1155/2016/9790169

Case Report Angelman-Like Syndrome: A Genetic Approach to Diagnosis with Illustrative Cases

Ho-Ming Luk

Clinical Genetic Service, Department of Health, Kowloon, Hong Kong

Correspondence should be addressed to Ho-Ming Luk; [email protected]

Received 15 December 2015; Revised 14 January 2016; Accepted 14 January 2016

Academic Editor: Christos Yapijakis

Copyright © 2016 Ho-Ming Luk. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Epigenetic abnormalities in 15q11-13 imprinted region and UBE3A mutation are the two major mechanisms for molecularly confirmed Angelman Syndrome. However, there is 10% of clinically diagnosed Angelman Syndrome remaining test negative. With the advancement of genomic technology like array comparative genomic hybridization and next generation sequencing methods, it is found that some patients of these test negative Angelman-like Syndromes actually have alternative diagnoses. Accurate molecular diagnosis is paramount for genetic counseling and subsequent management. Despite overlapping phenotypes between Angelman and Angelman-like Syndrome, there are some subtle but distinct features which could differentiate them clinically. It would provide important clue during the diagnostic process for clinicians.

1. Introduction Angelman-like Syndromes actually had alternative genetic diagnoses [6–8] which were important for counseling and Since the first description of Angelman Syndrome (AS) by management. Dr.Angelmanin1965[1],therewasagreatadvancementin Inthisreview,weuse4illustrativecasestoprovidethe understanding of its clinical features and molecular genetic overview of some Angelman-like Syndromes and highlight mechanism. AS is characterized by distinct facial gestalt, their difference with AS, so as to provide some guidance to developmental delay, absent speech, ataxic gait, seizure, and clinicians on the diagnostic workup when they encounter paroxysms of laughter [2]. The incidence reported was about such patients in their practice. 1/12,000 to 1/20,000 [3, 4] without racial predilection. The diagnosis of AS depends on the combination of clinical crite- ria and molecular and/or cytogenetic testing. The consensus 2. Illustrative Cases criteria for clinical diagnosis of AS were proposed in 2006 [5] whichincludedalistofcoreandassociatedfeatures.However, 2.1. Case 1. A 6-month-old girl was referred to genetic clinic the clinical manifestations of AS were highly heterogeneous for developmental delay. She was the second child of noncon- that would overlap with other diseases. Methylation study sanguineous Chinese couple, born at full term with birth on 15q11-13 imprinted region would identify 75–80% of AS weight of 3.83 kg. The perinatal history was unremarkable. that included maternal deletion, paternal uniparental disomy She was noted to have microcephaly (head circumference (UPD), and imprinting center defect. Further analysis of <3thpercentile,bodyweightandbodyheightat75th UBE3A gene would further confirm 10% of cases. How- percentile) and hypotonia at 3 months of age. Investiga- ever, there were still 5–10% of clinically diagnosed AS that tions including metabolic screening, muscle enzyme, and would be rendered “test negative.” With the advancement of computerized tomography of brain were normal. Physical medical genomic technology like array comparative genomic examination at 6 months of age showed microcephaly, flat hybridization (array CGH) and next generation sequencing, occiput, right divergent squint, and hypotonia. No syndromal it was now known that some patients of these “test negative” diagnosis could be ascertained at that time and she was 2 Case Reports in Genetics

(a) (b)

(c) (d)

Figure 1: Facial features of different Angelman-like Syndromes in this series. (a) FOXG1 related disease; (b) Rett Syndrome. (c) Mowat-Wilson Syndrome; (d) Phelan-McDermid Syndrome.

∗ regularly followed up in genetic clinic. She had epilepsy FOXG1{NP 005240.3}:p.[(Gly133Trpfs 68)];[=] which con- since she was 2 years of age and severe global delay at firmed the diagnosis of FOXG1 related congenital variant of developmental assessment. EEG showed nonspecific back- Rett Syndrome. ground slowing, but no epileptiform abnormalities. Brain Magnetic Resonance Image (MRI) showed mild thin- ning of corpus callosum without major structural defect. 2.2. Case 2. A 10-month-old girl was referred to genetic clinic There was no developmental regression, but she devel- for global delay. She was the first child of nonconsanguineous oped stereotypical hand movements (Figure 1), bruxism, Chinese couple, born at 38-week gestation with birth weight andoccasionaloutburstoflaugher.Basedonthecran- of 3.24 kg. Mother had gestational diabetes mellitus that iofacial features like microcephaly, flat occiput, divergent required insulin therapy. She had mild grade bilateral hearing squint, characteristic stereotypical hand movement, and out- impairment and left divergent squint diagnosed at birth. burst of laughter, Angelman/Rett Syndrome was suspected. Onfollow-up,shewasnotedtohavemicrobrachycephaly However, genetic investigations including methylation-spe- and global developmental delay (Figure 1). Brain MRI, cific multiplex ligation-dependent probe amplification (MS- metabolic screening, and array CGH were normal. She had MLPA) for AS, UBE3A gene, MECP2 gene, and array stereotypical handwashing movement since she was 1 year CGH studies were negative. Based on the MRI findings and old. There was no clinical or electrical seizure. Based early onset of microcephaly, FOXG1 related disease was on the craniofacial features like microbrachycephaly, wide suspected. FOXG1 gene test showed a de novo frameshift path- mouth, divergent squint, and behavioral phenotype, AS was ogenic mutation FOXG1{NM 005249.3}:c.[396 397ins26];[=]; initially suspected, but the methylation study and UBE3A Case Reports in Genetics 3

Table 1: Angelman-like Syndrome.

Chromatin-remodeling disorder Synaptopathies Unknown mechanism Syndrome Genes Syndrome Genes Syndrome Genes Phelan-McDermid Rett Syndrome/MECP2 duplication MECP2 Syndrome/22q13.3 deletion SHANK3 Pitt-Hopkins Syndrome TCF4 syndrome syndrome Mowat-Wilson Syndrome ZEB2 Christianson Syndrome SLC9A6 Kleefstra Syndrome/9q34.3 deletion EHMT1 HERC2 deficiency HERC2 syndrome MBD5 haploinsufficiency/2q23.1 MBD5 Adenylosuccinase deficiency ADSL deletion syndrome Koolen-de Vries Syndrome/17q23.31 KANSL1 CDKL5 syndrome CDKL5 deletion syndrome Congenital variant of Rett Syndrome FOXG1 MEF2C haploinsufficiency syndrome MEF2C Alpha-thalassemia/intellectual ATRX Ohtahara Syndrome STXBP1 disability syndrome Methylenetetrahydrofolate deficiency MTHFR

gene test were negative. Subsequently she had bruxism and during early infancy. Assessment at 1 year and 6 months developmental regression since she was 1 year and 6 months showed that she had moderate to severe grade developmental of age with loss of some motor and social skill. MECP2 study delay with autistic features. Baseline investigations included showed de novo nonsense mutation MECP2{NM 004992.3}: brain MRI and metabolic screening was normal. There was no ∗ c.[808C>T];[=];MECP2 {NP 004983.1}:p.[(Arg270 )];[=]that seizure, regression, or stereotypical hand movement. How- confirmed the diagnosis of Rett Syndrome. ever, she had occasional abnormal outburst of laughter. The head size was normal at 10–25th percentile. Despite the 2.3. Case 3. A5-year-oldgirlwasreferredtogeneticclinicfor fact that she had some behavioral features of AS, overall AS based on the facial dysmorphism. She was the first child clinical profile was not typical (Figure 1). Therefore array of nonconsanguineous Chinese couple, born at full term CGH was performed, which showed a de novo arr[Hg18] with birth weight of 2.9 kg. Perinatal history was unre- 22q13.31q13.33(45,355,784-49,522,658)x1. That means that a markable. She was noted to have dysmorphism and cardiac terminal deletion in chromosome 22 at band q13.31 region murmur during neonatal period. Echocardiogram showed with the size of 4.17 Mb included the SHANK3 gene; thus the patent ductus arteriosus and large secundum atrial septal diagnosis of Phelan-McDermid Syndrome was substantiated. defect. Total corrective operation was done at 1 year of age. Developmental assessment at 2 years of age showed severe 3. Summary and Conclusion grade developmental delay. Stereotypical hand movement, abnormal outburst of laughter, and ataxic gait were developed Loss of maternal inherited UBE3A gene predominantly afterward. Brain MRI showed mild thinning of corpus cal- expressed in the brain was the pathomechanism of AS. losum. Physical examination at genetic clinic showed head Only 90% of clinically diagnosed AS would have identifiable circumference at 3th percentile with body weight and body molecular defect. The remaining 10% were labeled as test neg- height at 10–25th percentile. There was facial dysmorphism, ative Angelman-like Syndrome. These Angelman-like Syn- namely, hypertelorism, medial flared eyebrows, mild over- dromes are actually separate disease entities that are not the hanging columella, pointed chin, and fleshy and uplifted variations of AS. However, due to overlapping clinical phe- earlobes (Figure 1). Based on facial gestalt, Mowat-Wilson notype, their differentiation is sometimes challenging. Over Syndrome rather than AS was suspected. ZEB2 gene study the last decade, there were many novel AS mimic diseases was performed. It showed a de novo pathogenic frameshift being discovered and summarized in Table 1 [6–8]. The { } mutation ZEB2 NM 014795.2 :c.[3335delACTT];[=];p.ZEB2 molecular basis for those AS mimic diseases could also be { } ∗ NP 055610.1 :p.[Tyr1112Cysfs 128][=]. Thus the diagnosis of classified into two emerging classes, namely, the chromatin- Mowat-Wilson Syndrome was substantiated. remodeling disorder and synaptopathies [6]. However, there werestillmanyofthemwithuncertainmechanismthathad 2.4. Case 4. A 2-year-old girl was referred from developmen- clinical phenotypes overlapping with AS. tal paediatrician for developmental delay with AS phenotype, The characteristic facial gestalt of AS included micro- namely, flat occiput and wide mouth. She was the first cephaly, flat occiput, divergent squint, wide mouth, and child of the nonconsanguineous Chinese couple, born at full widely spaced teeth. Given the phenotypic overlapping term with birth weight of 2.9 kg. The perinatal history was between the AS and Angelman-like Syndrome, clinical differ- unremarkable. She had hypotonia and feeding difficulties entiation was difficult. Despite this, there were some distinct 4 Case Reports in Genetics

Table 2: Differentiating clinical features among Angelman-like Syndromes.

AS Rett MWS FOXG1 KS PMS PHS CS CDKL5 MEF2C ARTX Microcephaly + + +++ ++++ + Seizure + + +++ ++++ Speech impairment + + +++ +++ + + Ataxia + ++++ Stereotypical hand movements +/− + + + ++ Tremulous/jerky limb movements + Happy predisposition + + + ++ Abnormal MRI ++ +++ Hyperventilation/apnea episode ++ Sleep disturbances + + ++ + Hirschsprung disease + Lack of purposeful hand use + Prominent jaw/chin ++ Wide mouth ++ + Upturned ear lobes + Genital anomalies + + Congenital heart disease ++ + Developmental regression +++ Persistent In male only In female Mild In male Others finger pad HbH in only overgrowth only Constipation blood smear AS:AngelmanSyndrome;MWS:Mowat-WilsonSyndrome;KS:KleefstraSyndrome; PMS: Phelan-McDermid Syndrome; PHS: Pitt-Hopkins Syndrome; CS: Christianson Syndrome; ARTX: alpha-thalassemia/intellectual disability syndrome.

features that could be useful for clinical diagnosis and guided Incase3,thediagnosiswasMowat-WilsonSyndromedue thefurthergenetictesting.Incase1,thediagnosiswasFOXG1 to loss of function in ZEB2 gene on chromosome 2q22.3. The related congenital variant of Rett Syndrome. It was first features resembling AS included moderate to severe grade reportedintheliteraturein2011[9].Thecoreclinicalfeatures intellectual disability, happy predisposition, epilepsy, and of FOXG1 related disease included early onset postnatal microcephaly [14]. However, congenital structural anomalies microcephaly, severe mental retardation, hypotonia, absent including Hirschsprung disease, congenital heart disease, and speech, dyskinesia, and corpus callosum hypogenesis [10, corpus callosum hypoplasia were far more common in 11]. The other reported MRI brain abnormalities included Mowat-Wilson Syndrome than in AS. The most distinguished delayed myelination and gyral simplification [11]. In this feature was the facial gestalt including hypertelorism, tele- case,theearlyonsetofpostnatalmicrocephalytogetherwith canthus, medial flared eyebrow, uplifted earlobes with central hypoplasia of corpus callosum was suggestive of FOXG1 depression, overhanging nasal tip, low inserted columella, related disease. Epilepsy was also common but relatively easy and prognathism [15]. It was well known that not all these to control as compared with CDKL5 related disorder [11], facial features were present during early life and diagnosis another Angelman-like Syndrome. Distinct EEG pattern couldbemissedduringearlychildhood. like high voltage slow delta activity and intermittent high- The diagnosis in case 4 was Phelan-McDermid Syndrome amplitude rhythmic theta activity would occasionally differ- (PMS). It was the first microdeletion syndrome that was entiate the AS from other Angelman-like Syndromes [8]. reported to mimic AS [16, 17]. The shared clinical features In case 2, the diagnosis was Rett Syndrome due to included moderate to severe grade global delay with absent MECP2 mutation. It was well reported that Rett Syndrome speech, hypotonia, and neonatal feeding difficulties that and AS have overlapping clinical features including seizures, happenedinourcase,butmildovergrowthwithlargehands, impaired sleep pattern, inappropriate laughter, and ataxia large ears, and dysplastic toenails would be the distinctive [12]. However, normal period of development during at least features for PMS [17, 18]. Posterior cranial fossa brain malfor- first6monthsoflifefollowedbydevelopmentalregres- mations were also well reported in PMS but not in AS. This sion was quite distinctive for Rett Syndrome. Unless the case illustrated that many microdeletion/microduplication epilepsy was poorly controlled, regression was unusual for syndromes were masqueraded Angelman-like Syndrome that AS. Although it was reported that AS had particular EEG array CGH should be the first investigation for them. pattern, there was also specific pattern in Rett Syndrome The clinical features of selected Angelman-like Syndrome like generalized background slowing and/or loss of occipital were summarized in Table 2. In terms of genetic testing for dominant rhythm, with further theta and delta slowing as the Angelman-like Syndrome, two categories of diseases based developmental regression continued [12, 13]. on the genetic mechanisms should be considered. These Case Reports in Genetics 5

Patient with Angelman-like Syndrome

Array CGH

Microdeletion/ microduplication syndrome

Genotyping of candidate gene Target gene panel

Mutation detected Mutation not detected

Alternative diagnosis Research studies like exome/ genome sequencing

Figure 2: The genetic diagnostic algorithm of Angelman-like Syndrome.

included microdeletion/microduplication syndrome and sin- [4] S. Steffenburg, C. L. Gillberg, U. Steffenburg, and M. Kyllerman, gle gene syndrome. Therefore, after methylation study and “Autism in Angelman syndrome: a population-based study,” UBE3A gene analysis, the first line of investigation for Pediatric Neurology,vol.14,no.2,pp.131–136,1996. Angelman-like Syndrome should be array CGH. If negative, [5] C.A.Williams,A.L.Beaudet,J.Clayton-Smithetal.,“Angelman either single gene analysis based on clinical phenotype or syndrome 2005: updated consensus for diagnostic criteria,” targeted gene panel by next generation sequencing should be American Journal of Medical Genetics Part A,vol.140,no.5,pp. pursued. The proposed diagnostic algorithm for Angelman- 413–418, 2006. like Syndrome was depicted in Figure 2. [6]C.A.Williams,A.Lossie,andD.Driscoll,“Angelmansyn- In conclusion, the Angelman-like Syndrome was not drome: mimicking conditions and phenotypes,” American Jour- nal of Medical Genetics,vol.101,no.1,pp.59–64,2001. uncommon. With the advancement of genomic testing, many [7] C. A. Williams, “Looks like Angelman syndrome but isn’t— emerging diseases have been identified with AS mimic phe- what is in the differential?” R.C.P.U. Newsletter,vol.22,no.1, notype. Accurate diagnosis is important as the pathogenesis, pp.1–5,2011. potential treatment, prognosis, and mode of inheritance [8]W.-H.Tan,L.M.Bird,R.L.Thibert,andC.A.Williams,“Ifnot among them are different. Recognition of distinct features Angelman, what is it? A review of Angelman-like syndromes,” among Angelman-like Syndrome would provide useful clue American Journal of Medical Genetics Part A,vol.164,no.4,pp. in diagnostic strategies. With the jurious use of new technolo- 975–992, 2014. gies like array CGH and next generation sequencing method, [9] F. Ariani, G. Hayek, D. Rondinella et al., “FOXG1 is responsible it is expected that more and more test negative Angelman-like for the congenital variant of Rett syndrome,” The American Syndromes would have definite molecular diagnosis. Journal of Human Genetics,vol.83,no.1,pp.89–93,2008. [10] F. Kortum,¨ S. Das, M. Flindt et al., “The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental Conflict of Interests retardation, absent language, dyskinesia, and corpus callosum hypogenesis,” Journal of Medical Genetics,vol.48,no.6,pp.396– The author declares that there is no conflict of interests 406, 2011. regarding the publication of this paper. [11] C. Philippe, D. Amsallem, C. Francannet et al., “Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females,” Journal of Medical Genetics,vol.47,no.1,pp.59–65, References 2010. [1] H. Angelman, “‘Puppet’ children. A report of three cases,” [12] J. L. Neul, W. E. Kaufmann, D. G. Glaze et al., “Rett syndrome: Developmental Medicine & Child Neurology,vol.7,no.6,pp. revised diagnostic criteria and nomenclature,” Annals of Neurol- 681–688, 1965. ogy, vol. 68, no. 6, pp. 944–950, 2010. [13] E. E. J. Smeets, K. Pelc, and B. Dan, “Rett syndrome,” Molecular [2] J. Clayton-Smith, “Clinical research on Angelman syndrome in Syndromology, vol. 2, no. 3–5, pp. 113–127, 2012. the United Kingdom: observations on 82 affected individuals,” [14] C. Zweier, C. T. Thiel, A. Dufke et al., “Clinical and mutational American Journal of Medical Genetics,vol.46,no.1,pp.12–15, spectrum of Mowat-Wilson syndrome,” European Journal of 1993. Medical Genetics, vol. 48, no. 2, pp. 97–111, 2005. [3] J. Clayton-Smith and M. E. Pembrey, “Angelman syndrome,” [15]L.Garavelli,M.Zollino,P.C.Mainardietal.,“Mowat-Wilson Journal of Medical Genetics,vol.29,no.6,pp.412–415,1992. syndrome: facial phenotype changing with age: study of 19 6 Case Reports in Genetics

Italian patients and review of the literature,” American Journal of Medical Genetics Part A,vol.149,no.3,pp.417–426,2009. [16]K.S.Precht,C.M.Lese,R.P.Spiroetal.,“Two22qtelomere deletions serendipitously detected by FISH,” Journal of Medical Genetics,vol.35,no.11,pp.939–942,1998. [17] K. Phelan and H. E. McDermid, “The 22q13.3 deletion syn- drome (Phelan-McDermid syndrome),” Molecular Syndromol- ogy,vol.2,no.3–5,pp.186–201,2012. [18] S. U. Dhar, D. del Gaudio, J. R. German et al., “22q13.3 deletion syndrome: clinical and molecular analysis using array CGH,” American Journal of Medical Genetics Part A,vol.152,no.3,pp. 573–581, 2010. M EDIATORSof INFLAMMATION

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